DK155713B - PROCEDURE FOR THE PREPARATION OF TABLETS WHICH THE ACTIVE SUBSTANCE IS A PHARMACEUTICAL ACTIVE SUBSTANCE OR A SWEET AGENT - Google Patents
PROCEDURE FOR THE PREPARATION OF TABLETS WHICH THE ACTIVE SUBSTANCE IS A PHARMACEUTICAL ACTIVE SUBSTANCE OR A SWEET AGENT Download PDFInfo
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- DK155713B DK155713B DK476180AA DK476180A DK155713B DK 155713 B DK155713 B DK 155713B DK 476180A A DK476180A A DK 476180AA DK 476180 A DK476180 A DK 476180A DK 155713 B DK155713 B DK 155713B
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- A—HUMAN NECESSITIES
- A21—BAKING; EDIBLE DOUGHS
- A21D—TREATMENT, e.g. PRESERVATION, OF FLOUR OR DOUGH, e.g. BY ADDITION OF MATERIALS; BAKING; BAKERY PRODUCTS; PRESERVATION THEREOF
- A21D2/00—Treatment of flour or dough by adding materials thereto before or during baking
- A21D2/08—Treatment of flour or dough by adding materials thereto before or during baking by adding organic substances
- A21D2/14—Organic oxygen compounds
- A21D2/18—Carbohydrates
- A21D2/181—Sugars or sugar alcohols
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
- A23L2/52—Adding ingredients
- A23L2/60—Sweeteners
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L27/00—Spices; Flavouring agents or condiments; Artificial sweetening agents; Table salts; Dietetic salt substitutes; Preparation or treatment thereof
- A23L27/30—Artificial sweetening agents
- A23L27/33—Artificial sweetening agents containing sugars or derivatives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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Description
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Den foreliggende opfindelse angår en fremgangsmåde til fremstilling af tabletter, som indeholder et fortyndingsmateriale, og hvor det aktive stof er et farmaceutisk aktivt stof eller et sødemiddel.The present invention relates to a process for the preparation of tablets containing a diluent and wherein the active substance is a pharmaceutically active substance or a sweetening agent.
Tabletter fremstilles konventionelt ved formning eller presning af 5 ingredienser og udgør et egnet middel til frigivelse af en aktiv farmaceutisk eller anden aktiv bestanddel.Tablets are conventionally prepared by molding or pressing 5 ingredients and constitute a suitable agent for releasing an active pharmaceutical or other active ingredient.
Til fremstilling af tabletter er det nødvendigt at have et fritflydende materiale, som har gode selvbindende egenskaber, og som ikke klæber sig fast til formnings- eller presningsudstyret. Sådanne 10 egenskaber opnås ved at anvende fortyndingsmidler og ét eller flere additiver, f.eks. bindemidler og/eller glittemidler, og ved styret granulering af bestanddelene. Nogle fortyndingsmidler har i sig selv bindings- og glitteegenskaber, men vil normalt kræve omhyggelig granulering.For the manufacture of tablets, it is necessary to have a free-flowing material which has good self-bonding properties and which does not adhere to the molding or pressing equipment. Such properties are obtained by using diluents and one or more additives, e.g. binders and / or lubricants, and by controlled granulation of the components. Some diluents inherently have bonding and glitter properties, but will usually require careful granulation.
15 Lactose er et almindeligt anvendt fortyndingsmiddel, med en acceptabel smag. Lactose alene har dog kun ringere klæbeevne og kræver normalt anvendelse af et bindemiddel. Desuden er det sædvanligvis påkrævet at anvende vådgranulering, som indebærer befugtning af ingredienserne, til opnåelse af et fugtigt, sammenhængende pulver, efterfulgt af 20 sigtning og styret tørring til opnåelse af granuler, der er egnet til fremstilling af tabletteringspulvere.Lactose is a commonly used diluent, with an acceptable taste. However, lactose alone has only poor adhesiveness and usually requires the use of a binder. In addition, it is usually required to use wet granulation, which involves wetting the ingredients, to obtain a moist, cohesive powder, followed by sieving and controlled drying to obtain granules suitable for preparing tableting powders.
Saccharose, især saccharose med lille partikelstørrelse, er også et egnet fortyndingsmiddel. Vådgranulering er sædvanlig, medmindre der anvendes specielt formulerede tabletteringsmaterialer såsom "DiPac", 25 en blanding af maltodextrin og saccharose, fremstillet af AmstarSucrose, especially small particle size sucrose, is also a suitable diluent. Wet granulation is customary unless specially formulated tableting materials such as "DiPac", a mixture of maltodextrin and sucrose made by Amstar, are used.
Corporation, USA, under anvendelse af en mikrokrystalliseringsproces kendt som transformering, hvilken imidlertid er en dyr fremstillingsproces.Corporation, USA, using a microcrystallization process known as transformation, which, however, is an expensive manufacturing process.
Andre fortyndingsmidler såsom stivelse, glucose, mannitol og sorbitol 30 kan også anvendes. Hvert af disse materialer har sine egne fordele til visse anvendelser, men som det er tilfældet med lactose og saccharose,Other diluents such as starch, glucose, mannitol and sorbitol 30 may also be used. Each of these materials has its own advantages for certain applications, but as is the case with lactose and sucrose,
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2 er det sædvanligvis nødvendigt at anvende bindemidler og/eller glittemidler sammen med styret granulering.2, it is usually necessary to use binders and / or lubricants together with controlled granulation.
Det har nu vist sig, at disaccharidet isomaltulose, der er billigere at fremstille end DiPac og det i eksempel 3 omtalte "Emdex", er særlig 5 egnet til anvendelse som et fortyndingsmateriale i tabletter.It has now been found that the disaccharide isomaltulose, which is cheaper to produce than DiPac and the "Emdex" mentioned in Example 3, is particularly suitable for use as a diluent in tablets.
Isomaltulose har hidtil kun fundet begrænset anvendelse; fx er det blevet foreslået anvendt til ølfremstilling (se Tysk Offentliggørelsesskrift No. 2344252), og stoffet er blevet brugt som et alternativ til isomaltose ved in vitro undersøgelser af 10 isomaltoseadsorption ("Some Recent Advances in Inborn Errors ofIsomaltulose has so far found only limited use; for example, it has been proposed to be used in beer making (see German Publication No. 2344252), and has been used as an alternative to isomaltosis in in vitro studies of 10 isomaltose adsorption ("Some Recent Advances in Inborn Errors of
Metabolism", Proceedings of Fourth Symposium of the Society for the Study of Inborn Errors of Metabolism, holdt i Dublin, juli 1966, udgivet som bog i 1968 af E. og S. Livingston, Ed Holt og Coffey på side 106 i bogen af Holzen vedrørende "Disaccharide Intolerances").Metabolism ", Proceedings of the Fourth Symposium of the Society for the Study of Inborn Errors of Metabolism, held in Dublin, July 1966, published as a book in 1968 by E. and S. Livingston, Ed Holt and Coffey on page 106 of the book by Holzen regarding "Disaccharide Intolerances").
15 Industrielt er stoffet før 1980 kun blevet anvendt som udgangsmateriale til fremstilling af isomaltitol (vide infra).15 Industrial prior to 1980, the substance was used only as a starting material for the production of isomaltitol (vide infra).
Overraskende kan isomaltulose give sammenhængende tabletter ved direkte presning med et glittemiddel, hvorved behovet for et bindemiddel undgås. Det er meget enkelt at fremstille tabletter under 20 anvendelse af krystallinsk isomaltulose fremstillet ved konventionel krystallisation af isomaltuloseopløsninger.Surprisingly, isomaltulose can provide cohesive tablets by direct pressing with a lubricant, thus avoiding the need for a binder. It is very simple to prepare tablets using crystalline isomaltulose prepared by conventional crystallization of isomaltulose solutions.
Opfindelsen angår derfor en fremgangsmåde til fremstilling af tabletter, hvor det aktive stof er et farmaceutisk aktivt stof eller et sødemiddel, og fremgangsmåden er ejendommelig ved, at en 25 tørblanding indeholdende 10-95% krystalliseret, ikke-granuleret isomaltulose samt ét eller flere aktive stoffer komprimeres.The invention therefore relates to a process for the preparation of tablets wherein the active substance is a pharmaceutically active substance or sweetener, and the process is characterized in that a dry mixture containing 10-95% crystallized, non-granulated isomaltulose and one or more active substances compressed.
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Isomaltulose er et reducerende disaccharid, som undertiden benævnes som palatinose. Det har strukturen: ch2oh H0-KJ_0 ho4_, •—\^·^>·Isomaltulose is a reducing disaccharide, sometimes referred to as palatinosis. It has the structure: ch2oh H0-KJ_0 ho4_, • - \ ^ · ^> ·
'I-\ CH20H'I- \ CH 2 OH
HOHAY
og er mere systematisk kendt som 6-0-(a-D-glucopyranosyl)-D-5 fructofuranose.and is more systematically known as 6-O- (α-D-glucopyranosyl) -D-5 fructofuranose.
Historisk blev isomaltulose først nævnt i en artikel fra 1952 (J.Historically, isomaltulose was first mentioned in a 1952 article (J.
Amer. Chem. Soc. 74, 3202 (1952)) som et biprodukt fra en fermenterende mikroorganisme, Leuconostoc mesenteroides. Senere arbejder, der blev offentliggjort i henholdsvis 1956 og 1960 (J. Amer. Chem.Amer. Chem. Soc. 74, 3202 (1952)) as a by-product of a fermenting microorganism, Leuconostoc mesenteroides. Later works published in 1956 and 1960 respectively (J. Amer. Chem.
10 Soc. 78, 2514 (1956) og J. Org. Chem. 25, 1062 (1969)), bekræftede dannelsen af isomaltulose som et biprodukt ved Leuconostoc mesenteroides' syntese af dextran ud fra saccharose.Soc. 78, 2514 (1956) and J. Org. Chem. 25, 1062 (1969)), confirmed the formation of isomaltulose as a by-product of Leuconostoc mesenteroides' synthesis of dextran from sucrose.
Den bakterielle omdannelse af saccharose til isomaltulose af Prota-minobacter rubrum beskrives i tysk patentskrift nr. 1.049.800 i navnet 15 Suddeutsche Zucker-Aktiengesellschaft. Andre bakterier kan anvendes til opnåelse af omdannelsen af saccharose til isomaltulose, og i britisk patentskrift nr. 1.429.334 (som svarer til tysk patentskrift nr. 2.217.628) nævner samme firma, at Serratia plymuthica også er egnet.The bacterial conversion of sucrose to isomaltulose by Prota-minobacter rubrum is described in German patent specification 1,049,800 in the name of 15 Suddeutsche Zucker-Aktiengesellschaft. Other bacteria can be used to achieve the conversion of sucrose to isomaltulose, and in British Patent No. 1,429,334 (which corresponds to German Patent No. 2,217,628) the same company mentions that Serratia plymuthica is also suitable.
20 Britisk patentskrift nr. 1.429.334 angår først og fremmest fremstil lingen af isomaltitol (a-D-glucopyranosyl-l,6-sorbitol) ud fra iso- 4British Patent Specification No. 1,429,334 relates primarily to the preparation of isomaltitol (α-D-glucopyranosyl-1,6-sorbitol) from iso-4
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maltulose ved katalytisk hydrogenering. I praksis opnås der ved hydrogeneringen en blanding, som også indeholder ct-D-glucopyranosyl-1,6-mannitol; denne blanding forhandles som et kaloriefattigt sødemiddel under varemærket "Palatinit". Dette skrift beskriver dog 5 kun, at den polyvalente alkohol isomaltitol efter granulering kan formes til tabletter. Dette antyder dog ikke, at den fra isomaltitol forskellige forbindelse isomaltulose uden granulering eller komprimering direkte kan tabletteres.maltulose by catalytic hydrogenation. In practice, the hydrogenation yields a mixture which also contains ct-D-glucopyranosyl-1,6-mannitol; this mixture is marketed as a low calorie sweetener under the trademark "Palatinite". However, this specification discloses only that the polyhydric alcohol isomaltitol after granulation can be formed into tablets. However, this does not suggest that the compound different from isomaltitol can be directly tableted without isomaltulose without granulation or compression.
I europæisk patentansøgning nr. 0001099 beskriver Bayer Aktien-10 gesellschaft en fremgangsmåde til kontinuerlig fermentation af mikro organismer, f.eks. Protaminobacter rubrum eller Serratia plymuthica, med samtidig omdannelse af saccharose til isomaltulose. Også her fremstilles isomaltulose med henblik på at blive hydrogeneret til opnåelse af det kaloriefattige sødemiddel.In European Patent Application No. 0001099, Bayer Aktiengesellschaft describes a process for continuous fermentation of microorganisms, e.g. Protaminobacter rubrum or Serratia plymuthica, with concomitant conversion of sucrose to isomaltulose. Here again, isomaltulose is prepared to be hydrogenated to obtain the low calorie sweetener.
15 Hidtil har hydrogeneringen af isomaltulose til et kaloriefattigt søde middel åbenbart været den vigtigste anvendelse for forbindelsen.So far, the hydrogenation of isomaltulose to a low-calorie sweetener has obviously been the most important use for the compound.
Ved den foreliggende opfindelse tilvejebringes en fremgangsmåde til fremstilling af tabletter, som indeholder isomaltulose som fortyndingsmaterialet eller som et fortyndingsmateriale.The present invention provides a process for the preparation of tablets containing isomaltulose as the diluent or diluent.
20 Det har nu vist sig, at isomaltulose har en bestemt kombination af fysiske og andre egenskaber, som gør det særlig egnet til anvendelse som et fortyndingsmateriale i tabletter. Især har isomaltulose bedre opløselighed i vand end lactose, kræver ingen omhyggelig, styret granulering og kan formes til tabletter ved direkte presning med et 25 glittemiddel.It has now been found that isomaltulose has a particular combination of physical and other properties which makes it particularly suitable for use as a diluent in tablets. In particular, isomaltulose has better solubility in water than lactose, requires no careful, controlled granulation, and can be formed into tablets by direct pressing with a lubricant.
Desuden har isomaltulose en behagelig, ikke særlig sød, temmelig mild smag og tillader andre ingredienser at udøve en smagsvirkning.In addition, isomaltulose has a pleasant, not very sweet, rather mild taste and allows other ingredients to exert a flavor effect.
Det har vist sig, at isomaltulose har de i følgende tabel viste egenskaber:It has been found that isomaltulose has the properties shown in the following table:
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Isomaltulose-egenskaberIsomaltulose properties
Opløselighed ved 30° C i vand 46 g/100 ml viskositet ved 25°C, 50% w/v, HgO 6 cp 5 [a]20° ved 1% w/v + 97°Solubility at 30 ° C in water 46 g / 100 ml viscosity at 25 ° C, 50% w / v, HgO 6 cp 5 [a] 20 ° at 1% w / v + 97 °
smeltepunkt 118-122“Cmp 118-122 ° C
mutarotation (90 timer ved 58°Cmutarotation (90 hours at 58 ° C
i 2M HC1) nihil reducerings evne 58-62% af glucosens 10 reduceringsevne ækvilibrium relative ligevægtsfugtighed (ved 80% og 22°C) 25-32% vand sødhed (i relation til saccharose- sødhed ved 7% w/v i vand) 0,37 15 Foruden at drage fordel af disse påviselige egenskaber hos isomaltulose har den foreliggende opfindelse påvist uventede gunstige egenskaber hos isomaltulose. Således viser tabletter, hvori der anvendes isomaltulose som fortyndingsmiddel, ofte mindre tendens til at danne fint materiale under håndtering, end det er tilfældet ved 20 håndtering af lignende tabletter, hvor der anvendes lactose som fortyndingsmiddel. Mere generelt er det overraskende at finde, at isomaltulose er en egnet erstatning for lactose, især da andre, mere almindelige saccharider ikke kan anvendes til direkte tablettering. Isomaltulose ser ud til at have usædvanlig god bindingsevne, når det 25 formes til tabletter.in 2M HCl) nihil reducing ability 58-62% of glucose reducing equilibrium relative equilibrium humidity (at 80% and 22 ° C) 25-32% water sweetness (relative to sucrose sweetness at 7% w / vi water) 0, In addition to taking advantage of these detectable properties of isomaltulose, the present invention has demonstrated unexpected beneficial properties of isomaltulose. Thus, tablets using isomaltulose as a diluent often show less tendency to form fine material during handling than does the case with similar tablets using lactose as diluent. More generally, it is surprising to find that isomaltulose is a suitable substitute for lactose, especially as other, more common saccharides cannot be used for direct tableting. Isomaltulose appears to have exceptionally good bonding ability when formed into tablets.
Isomaltulose kan anvendes som fortyndingsmiddel i forskellige fysiologisk aktive ingredienser. Det kan ikke alene anvendes i farmaceutiske tabletter, men også i andre tabletter, der indeholder andre slags fysiologisk aktive ingredienser, herunder smagsstoffer.Isomaltulose can be used as a diluent in various physiologically active ingredients. It can be used not only in pharmaceutical tablets but also in other tablets containing other kinds of physiologically active ingredients, including flavors.
30 F.eks. kan isomaltulose anvendes som fortyndingsmiddel i sødetabletter, hvor den aktive bestanddel er et sødemiddel med høj sødeevne såsom saccharin eller det søde protein thaumatin, som 6For example, For example, isomaltulose can be used as a diluent in sweetened tablets, wherein the active ingredient is a high sweetening sweetener such as saccharin or the sweet protein thaumatin which
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ekstraheres fra Thaumatococcus danielii, og som forhandles under varemærket Talin . Sådanne tabletter kan f.eks. anvendes til at søde varme drikke med.extracted from Thaumatococcus danielii, which is marketed under the trademark Talin. Such tablets may e.g. used to sweeten hot drinks with.
Helt generelt kan isomaltulose i overensstemmelse med fremgangsmåden 5 ifølge den foreliggende opfindelse anvendes som hel eller delvis erstatning af andre fortyndingsmaterialer i konventionelle formuleringer. Det ideelle vil være være 100% rent isomaltulose, opnået ved gentagen krystallisation af materialet fremstillet ved bakteriel omdannelse af saccharose under anvendelse af f.eks. de i 10 tysk patentskrift nr. 1.049.800, britisk patentskrift nr. 1.492.334 eller europæisk patentansøgning nr. 0001099 beskrevne fremgangsmåder.In general, in accordance with the method 5 of the present invention, isomaltulose can be used as a complete or partial replacement of other diluents in conventional formulations. The ideal would be 100% pure isomaltulose, obtained by repeated crystallization of the material prepared by bacterial conversion of sucrose using e.g. 10 German Patent No. 1,049,800, British Patent No. 1,492,334 or European Patent Application No. 0001099.
Det har dog vist sig, at der opnås acceptable resultater, når der anvendes et én gang krystalliseret materiale. Således kan isomaltulose i praksis være urent, indeholdende op til 10, 20 eller endog højere 15 procenter af andre saccharider og ledsagestoffer.However, it has been found that acceptable results are obtained when a once crystallized material is used. Thus, in practice, isomaltulose can be unclean, containing up to 10, 20 or even higher 15 percent of other saccharides and accompanying substances.
I beskrivelsen til dansk patentansøgning nr. 4760/80, som også kræver prioritet fra 7. november 1979, beskrives en hidtil ukendt fremgangsmåde under anvendelse af immobiliseret isomaltulose-enzym-systemer til omdannelse af saccharose. Det umiddelbare produkt af 20 denne fremgangsmåde er en isomaltuloseopløsning, som også indeholder saccharose og biprodukter. Der kan anvendes simpel krystallisation ved konventionelle koncentrerings- og afkølingsprocedurer til opnåelse af krystaller med et indhold af isomaltulose på 90% eller derover.The specification for Danish patent application No. 4760/80, which also requires priority from November 7, 1979, describes a novel method using immobilized isomaltulose enzyme systems for conversion of sucrose. The immediate product of this process is an isomaltulose solution which also contains sucrose and by-products. Simple crystallization can be used in conventional concentration and cooling procedures to obtain crystals having an isomaltulose content of 90% or more.
Sådanne krystaller er særlig egnet til fremstilling af tabletter.Such crystals are particularly suitable for the preparation of tablets.
25 De her omhandlede tabletter kan have en hvilken som helst af de sædvanlige former, runde, firkantede eller andet, som afhængigt af det anvendte udstyr. Isomaltuloseindholdet ligger i området fra 10 til 95%. Foruden de aktive ingredienser, der sædvanligvis udgør 3 - 90% af de her omhandlede tabletter, og foruden de andre fortyndingsmidler 30 såsom lactose kan tabletterne endvidere indeholde kendte tabletteringsadditiver, f.eks. til farvning af tabletterne, for at fremme binding af ingredienserne, til opnåelse af brusen eller til at fremme frigørelse af tabletterne fra en tabletteringsmaskine.The tablets herein may be of any of the usual shapes, round, square or otherwise, as depending on the equipment used. The isomaltulose content ranges from 10 to 95%. In addition to the active ingredients, which usually constitute 3 to 90% of the tablets herein, and in addition to the other diluents 30 such as lactose, the tablets may further contain known tableting additives, e.g. for coloring the tablets, for promoting the binding of the ingredients, for obtaining the effervescent or for promoting the release of the tablets from a tableting machine.
Fagmanden vil være kendt med sådanne additiver (f.eks. farvemidler, 7Those skilled in the art will be familiar with such additives (e.g., coloring agents, 7
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gummi arabicum, natriumstearat og stivelse), og yderligere oplysninger er ikke nødvendige for at give en tilstrækkelig beskrivelse af den foreliggende opfindelse. Tabletter ifølge opfindelsen vejer sædvanligvis fra 5 mg til 5 g, idet 50 - 500 mg foretrækkes.gum arabic, sodium stearate and starch), and further information is not necessary to provide a sufficient description of the present invention. Tablets according to the invention usually weigh from 5 mg to 5 g, with 50-500 mg being preferred.
5 Fremstilling af de her omhandlede tabletter kan udføres under anvendelse af kendte teknikker. Sædvanligvis fremstilles en findelt blanding af isomaltulosen og andre ingredienser, efterfulgt af formning eller presning.Preparation of the present tablets may be carried out using known techniques. Usually, a finely divided mixture of isomaltulose and other ingredients is prepared, followed by molding or pressing.
I modsætning til lactose og saccharose kan isomaltulosekrystaller 10 fremstillet ved sædvanlige krystallisationsfremgangsmåder give tilfredsstillende tabletter ved direkte presning efter blanding med et glittemiddel og den ønskede aktive bestanddel. Ved den foreliggende opfindelse tørblandes isomaltulosekrystaller fremstillet ved krystallisation ud fra en vandig opløsning med et glittemiddel såsom 15 et fedtsyresalt og med den aktive bestanddel, der skal tabletteres.In contrast to lactose and sucrose, isomaltulose crystals 10 prepared by conventional crystallization processes can provide satisfactory tablets by direct pressing after mixing with a lubricant and the desired active ingredient. In the present invention, isomaltulose crystals prepared by crystallization are dry blended from an aqueous solution with a lubricant such as a fatty acid salt and with the active ingredient to be tableted.
Derpå udføres presning af den tørre blanding, hvorved der fås tabletter. Generelt giver denne fremgangsmåde fordele sammenlignet med de foranstaltninger, der er nødvendige til fremstilling af tabletter, når der anvendes andre, almindelige fortyndingsmidler.Then, the dry mixture is compressed to give tablets. In general, this approach provides advantages over the measures needed to make tablets when using other common diluents.
20 Isomaltulose er acceptabel til anvendelse i medicinalvarer. Som tidligere nævnt, er det blevet anvendt som et alternativ til isomaltose ved in vitro undersøgelser af isomaltoseadsorption. Som et resultat af de kliniske forsøg har det vist sig, at isomaltulose let hydrolyseres af et enzymcomplex i tarmkanalen hos mennesker, og at 25 monosaccharidbestanddelene (fructose og glucose) adsorberes, metaboliseres og på anden måde opfører sig som fructose og glucose afledt af saccharose.Isomaltulose is acceptable for use in pharmaceutical products. As previously mentioned, it has been used as an alternative to isomaltose in in vitro studies of isomaltose adsorption. As a result of the clinical trials, it has been found that isomaltulose is readily hydrolyzed by an enzyme complex in the human intestinal tract and that the monosaccharide components (fructose and glucose) are adsorbed, metabolized and otherwise behave as fructose and glucose derived from sucrose.
Desuden indicerer foreløbige undersøgelser, at selv om isomaltulose metaboliseres af Streptococcus mutans (den bakterie, der menes at 30 forårsage tandcaries), dannes der kun lidt plaque, hvis det over hovedet dannes. Der er således god grund til at tro, at isomaltulose er ikke-cariogen (dvs. en forbindelse, som ikke inducerer dannelse af tandcaries).In addition, preliminary studies indicate that although isomaltulose is metabolized by Streptococcus mutans (the bacterium that is thought to cause dental caries), little plaque is formed if it is formed over the head. Thus, there is good reason to believe that isomaltulose is non-cariogenic (ie, a compound that does not induce the formation of dental caries).
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Den foreliggende opfindelse illustreres ved følgende eksempler. I disse eksempler er isomaltulose et krystallinsk materiale, som er mindst 90% rent, og som er fremstillet ved fremgangsmåden ifølge eksempel 1 i beskrivelsen til dansk patentansøgning nr. 4760/80.The present invention is illustrated by the following examples. In these examples, isomaltulose is a crystalline material which is at least 90% pure and prepared by the method of Example 1 of the specification for Danish Patent Application No. 4760/80.
5 Isomaltulose fremstillet ved andre metoder kan anvendes i stedet for.5 Isomaltulose prepared by other methods can be used instead.
EKSEMPEL 1EXAMPLE 1
Codeintabletter indeholdende 11,5% isomaltulose 80 g acetylsalicylsyre, 80 g phenacetinpulver, 2,5 g codeinphosphat, 23 g isomaltulose, 12,5 g gummi arabicum og 2 g magnesiumstearat blev 10 tørblandet for at give et fritflydende-tabletteringspulver. Tabletter blev formet ved direkte presning, hvilke tabletter var hårde, sammenhængende og letopløselige.Codeine tablets containing 11.5% isomaltulose 80 g of acetylsalicylic acid, 80 g of phenacetin powder, 2.5 g of codeine phosphate, 23 g of isomaltulose, 12.5 g of gum arabic and 2 g of magnesium stearate were mixed dry to give a free-flowing tableting powder. Tablets were formed by direct pressing, which tablets were hard, cohesive and easily soluble.
EKSEMPEL 2.EXAMPLE 2.
Sammenligning med lactose.Comparison with lactose.
15 i) Direkte presning.15 i) Direct pressing.
50 g isomaltulose, 4 g gummi arabicum, 1 g natriumstearat og 13 g saccharin tørblandes, hvorved der fås et fritflydendé tabletteringspulver. Tabletter formes ved direkte presning af pulveret. Der opstår ingen problemer med hensyn til klæbning under 20 presningen, og de resulterende tabletter er hårde, sammenhængende og alligevel letopløselige.Mix 50 g of isomaltulose, 4 g of gum arabic, 1 g of sodium stearate and 13 g of saccharin to give a free-flowing tableting powder. Tablets are formed by direct pressing of the powder. No problems with adhesion occur during pressing and the resulting tablets are hard, cohesive and yet easily soluble.
I modsætning hertil var det ikke muligt at producere sammenhængende tabletter under anvendelse af enten 50 g lactose eller 50 g flormelis i stedet for isomaltulosen.In contrast, it was not possible to produce coherent tablets using either 50 g of lactose or 50 g of icing instead of the isomaltulose.
DK 155713 BDK 155713 B
9 ii) Forenklet direkte presning.9 ii) Simplified direct pressing.
Et tabletteringspulver baseret på isomaltulose fremstilles på samme måde som i eksempel 2 (i), med undtagelse af, at bindemidlet (gummi arabicum) udelades. Til trods for udeladelse af bindemidlet er 5 fremstillingen af tabletterne stadigvæk vellykket ved direkte presning.An isomaltulose tableting powder is prepared in the same manner as in Example 2 (i), except that the binder (gum arabic) is omitted. Despite omitting the binder, the preparation of the tablets is still successful by direct pressing.
Der kan ikke fremstilles tabletter ved anvendelse af lactose eller flormelis i stedet for isomaltulosen.Tablets cannot be made using lactose or icing instead of isomaltulose.
EKSEMPEL 3 10 Aspirintabletter til børnEXAMPLE 3 10 Aspirin tablets for children
Den følgende formulering blev anvendt til evaluering af seks fortyndingsmidler:The following formulation was used to evaluate six diluents:
Aspirin (20 mesh «= 850/zm) 40,5 gAspirin (20 mesh «= 850 µm) 40.5 g
Fortyndingsmiddel** 50,0 g 15 Stivelse* 5,0 gDiluent ** 50.0 g 15 Starch * 5.0 g
Magnesiumstearat 4,0 gMagnesium stearate 4.0 g
Smagsstof qsFlavoring qs
Laing National "Crystal Gum S" tabletteringsstivelse ** Fortyndingsmidler: (i) Isomaltulose - krystalliseret materiale 20 (ii) DiPac - Amstar (iii) Emdex (tabletteringssukkerstof fremstillet af mikrokrystallinsk dextrose og maltodextrin) -EJ Mendell (iv) Lactose - BDH Drug Houses 25 (v) Flormelis (pulveriseret saccharose) -Laing National "Crystal Gum S" Tablets Starch ** Diluents: (i) Isomaltulose - Crystallized Material 20 (ii) DiPac - Amstar (iii) Emdex (Tablets Sugar Made from Microcrystalline Dextrose and Maltodextrin) -EJ Mendell (iv) Lactose - BDH Drug Houses (V) Icing (powdered sucrose) -
T & L Refineries (vi) Vandfrit dextrose - BDHT&L Refineries (vi) Anhydrous Dextrose - BDH
DK 155713BDK 155713B
1010
Fremgangsmåde: (a) Aspirinet blev blandet med fortyndningsmidlet, der skulle afprøves, og der blev taget forholdsregler mod optagelse af fugtighed. Smagsstoffet blev sat til stivelsen under omhyggelig omrøring.Procedure: (a) The aspirin was mixed with the diluent to be tested and precautionary measures were taken to absorb moisture. The flavor was added to the starch with careful stirring.
5 Derefter blev magnesiumstearatet sat til stivelsen, og denne kombination blev blandet under omrystning med aspirin-f or tyndingsmiddelblandingen.Then, the magnesium stearate was added to the starch and this combination was mixed with shaking with the aspirin or thinner mixture.
(b) Blandingens flydbarhed blev evalueret ved måling af tiden for strømning gennem en tragtformet strømningsmåler med 9,5 mm (3/8 tomme) 10 åbning uden vibrering.(b) The flowability of the mixture was evaluated by measuring the flow time through a 9.5mm (3/8 inch) funnel-shaped flow meter without vibration.
Den tid, det tog for 100 g af tabletteringsblandingen at strømme gennem tragtens 9,5 mm-åbning, blev målt.The time taken for 100 g of the tableting mixture to flow through the 9.5 mm opening of the funnel was measured.
Fortyndingsmiddel Tid (sekunder)Diluent Time (seconds)
Isomaltulose 38 15 DiPac 34Isomaltulose 38 15 DiPac 34
Emdex 42Emdex 42
Lactose Ingen strømningLactose No flow
Flormelis Ingen strømningIcing No flow
Vandfrit dextrose Ingen strømning 20 "Ingen strømning" betyder, at blandingen ikke kunne flyde frit gennem tragten uden omrystning.Anhydrous Dextrose No Flow 20 "No flow" means that the mixture could not flow freely through the funnel without shaking.
Isomaltulose er tydeligvis sammenlignelig med de specielt fremstillede produkter DiPac og Emdex, og stoffet er tydeligvis bedre end lactose, flormelis eller vandfrit dextrose.Isomaltulose is clearly comparable to the specially made products DiPac and Emdex, and the substance is clearly better than lactose, icing or anhydrous dextrose.
25 (c) Tabletter blev fremstillet under anvendelse af en 6,35 mm (1/4 tomme) stempel med plan endeflade, og der blev opnået følgende resultater:(C) Tablets were prepared using a 6.35 mm (1/4 inch) flat end piston and the following results were obtained:
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11 (i) Isomaltulose: Tabletfremstilling blev heldigt gennemført.11 (i) Isomaltulose: Tablet preparation was successfully completed.
Tabletterne slap pressestemplet let.The tablets easily released the plunger.
5 Godt skinnende udseende5 Good shiny look
God fuldstændighed (ii) DiPac: Som for (i) (iii) Emdex: Som for (i) (iv) Lactose: Uregelmæssig strømning gav 10 problemer med hensyn til tabletf uldstændighed.Good completeness (ii) DiPac: As for (i) (iii) Emdex: As for (i) (iv) Lactose: Irregular flow caused 10 problems with tablet completeness.
Normalt blev der ikke opnået sammenhængende tabletter. Tabletmaskinen viste 15 tilbøjelighed til klæbning.Usually, no coherent tablets were obtained. The tablet machine showed 15 tendency to stick.
(v) Flormelis: Som for (iv) (vi) Vandfrit dextrose: Som for (iv)(v) Icing: As for (iv) (vi) Anhydrous dextrose: As for (iv)
Det er igen klart, at isomaltulose er sammenlignelig med DiPac og Emdex og er de andre fortyndingsmidler overlegen.Again, it is clear that isomaltulose is comparable to DiPac and Emdex and the other diluents are superior.
20 (d) Tabletvægtene var: Isomaltulose 151 mg(D) The tablet weights were: Isomaltulose 151 mg
DiPac 155 mgDiPac 155 mg
Emdex 155 mgEmdex 155 mg
Evaluering af vægten af de andre tabletter var ikke mulig på grund af fremstillingsvanskelighederne (jf. c).Evaluation of the weight of the other tablets was not possible due to the manufacturing difficulties (cf. c).
25 (e) Derefter blev tablethårdheden evalueret. Til objectiv afprøvning blev tabletterne vibreret i en beholder i én time. Det procentiske vægttab, som følger af slid, blev noteret og var som følger: 12(E) Thereafter, tablet hardness was evaluated. For objective testing, the tablets were vibrated in a container for one hour. The percentage weight loss resulting from wear was noted and was as follows:
DK 155713 BDK 155713 B
Isomaltulose 3,2%Isomaltulose 3.2%
DiPac 0,5%DiPac 0.5%
Emdex 0,5%Emdex 0.5%
Det er således klart, at selv om DiPac og Emdex giver lidt hårdere 5 tabletter end isomaltulose, er tablethårdheden, der opnås med isomaltulose ikke desto mindre tilfredsstillende.Thus, it is clear that although DiPac and Emdex provide slightly harder 5 tablets than isomaltulose, the tablet hardness achieved with isomaltulose is nonetheless satisfactory.
EKSEMPEL 4EXAMPLE 4
Ascorbinsyretabletter Følgende formulering blev anvendt under anvendelse af samme 10 fremgangsmåde som for eksempel 3:Ascorbic Acid Tablets The following formulation was used using the same procedure as Example 3:
Ascorbinsyre 55,0 gAscorbic acid 55.0 g
Fortyndings-middel 63,5 gDiluent 63.5 g
Magnesium- 15 stearat 1.0 gMagnesium stearate 1.0 g
Igen viste isomaltulose god ydeevne med hensyn til flydbarhed, men ikke så god ydeevne med hensyn til tablethårdhed.Again, isomaltulose showed good performance in terms of flowability, but not as good in terms of tablet hardness.
Flydbarhed 100 g gennem 9,5 mm-åbning, ingen omrystning 20 Isomaltulose 43 sekunderFlowability 100 g through 9.5 mm opening, no shaking 20 Isomaltulose 43 seconds
DiPac 39 sekunderDiPac 39 seconds
Emdex 46 sekunderEmdex 46 seconds
Dextrose, Lactose, Sucrose Omrystning nødvendigDextrose, Lactose, Sucrose Shake required
DK 155713 BDK 155713 B
13 Vægttab ved vibrering i én time:13 Weight loss when vibrating for one hour:
Isomaltulose 1,8%Isomaltulose 1.8%
DiPac 0,4%DiPac 0.4%
Emdex 0,3% 5 Igen, var tabletter med isomaltulose skinnende, hårde og af godt udseende. Selv om tabletterne ikke var så hårde som tabletterne, der blev fremstillet med de specieltformulerede fortyndingsmidler DiPac og Emdex, var isomaltulose generelt klart bedre end dextrose, lactose og sucrose, og gav fuldt tilfredsstillende resultater.Emdex 0.3% 5 Again, isomaltulose tablets were shiny, hard and of good appearance. Although the tablets were not as hard as the tablets prepared with the specially formulated diluents DiPac and Emdex, isomaltulose was generally clearly superior to dextrose, lactose and sucrose, and gave fully satisfactory results.
10 EKSEMPEL 5EXAMPLE 5
Vitamin C-tabletter indeholdende lactose som anden diluent 46 g ascorbinsyre, 30 g isomaltulose, 23 g lactose og 1 g magnesiumstearat blev tørblandet for at give et fritflydende tabletteringspulver. Tabletter blev formet ved direkte presning under 15 anvendelse af et 6,35 mm (0,25 tomme) stempel med plan endeflade.Vitamin C tablets containing lactose as a second diluent 46 g of ascorbic acid, 30 g of isomaltulose, 23 g of lactose and 1 g of magnesium stearate were dry mixed to give a free-flowing tableting powder. Tablets were formed by direct pressing using a 6.35 mm (0.25 inch) flat end piston.
Tabletterne var hårde og sammenhængende og var letopløselige i vand.The tablets were hard and cohesive and readily soluble in water.
Claims (5)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB7938562 | 1979-11-07 | ||
| GB7938562 | 1979-11-07 | ||
| GB8021825 | 1980-07-03 | ||
| GB8021825 | 1980-07-03 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK476180A DK476180A (en) | 1981-05-08 |
| DK155713B true DK155713B (en) | 1989-05-08 |
| DK155713C DK155713C (en) | 1989-09-25 |
Family
ID=26273463
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK476180A DK155713C (en) | 1979-11-07 | 1980-11-07 | PROCEDURE FOR THE PREPARATION OF TABLETS WHICH THE ACTIVE SUBSTANCE IS A PHARMACEUTICAL ACTIVE SUBSTANCE OR A SWEET AGENT |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US4572916A (en) |
| EP (1) | EP0028905B1 (en) |
| CA (1) | CA1157772A (en) |
| DE (1) | DE3062775D1 (en) |
| DK (1) | DK155713C (en) |
| IE (1) | IE50399B1 (en) |
| NO (1) | NO157882C (en) |
Families Citing this family (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5771377A (en) * | 1980-10-23 | 1982-05-04 | Mitsui Seito Kk | Sweetening agent having low cariogenicity |
| US4870059A (en) * | 1985-11-27 | 1989-09-26 | Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo | Dehydration of hydrous matter with anhydrous maltose |
| JPH0710342B2 (en) * | 1985-12-26 | 1995-02-08 | 株式会社林原生物化学研究所 | Method for dehydrating hydrated material with anhydrous aldohexose |
| JPH0710343B2 (en) * | 1985-12-26 | 1995-02-08 | 株式会社林原生物化学研究所 | Method for dehydrating hydrated substance with anhydrous lactoitol |
| JPH0710344B2 (en) * | 1985-12-26 | 1995-02-08 | 株式会社林原生物化学研究所 | Method for dehydrating hydrated substance by anhydrous glycosyl fructose |
| FR2613619B1 (en) * | 1987-04-07 | 1993-10-15 | Recherche Informatique Pharmacie | DRUGS, DIETETIC PRODUCTS OR HYGIENE PRODUCTS IN THE FORM OF POWDER COMPOSITIONS OBTAINED BY ADSORPTION OF ACTIVE INGREDIENTS ON A FAST-DISSOLVING SUGAR |
| GB8907007D0 (en) * | 1989-03-28 | 1989-05-10 | Tate & Lyle Plc | Sucralose compositions |
| US4886677A (en) * | 1987-08-25 | 1989-12-12 | Mitsubishi Kasei Corporation | Surface-modified meso-erythritol composition |
| US4971798A (en) * | 1989-11-30 | 1990-11-20 | Miles Inc. | Hard confections containing hydrogenated isomaltulose and medicinally active ingredient |
| US5204115A (en) * | 1990-12-12 | 1993-04-20 | Suomen Xyrofin Oy | Directly compressible xylitol and method |
| DE19639343C2 (en) * | 1996-09-25 | 1998-10-08 | Suedzucker Ag | Comprimate containing a sweetener mixture |
| DE19943491B4 (en) | 1999-09-10 | 2010-04-01 | Südzucker AG Mannheim/Ochsenfurt | Improved compressed |
| DE19943496C1 (en) * | 1999-09-10 | 2001-05-17 | Suedzucker Ag | Directly compressible raw material for compressed air |
| JP4860840B2 (en) * | 2001-05-14 | 2012-01-25 | 三井製糖株式会社 | Agent for maintaining concentration and attention and food and drink containing the agent |
| FR2826549A1 (en) * | 2001-06-28 | 2003-01-03 | Roquette Freres | PROCESS FOR THE PREPARATION OF A COMPRESSED EDULCORANT TABLET AND A COMPRESSED EDULCORANT THUS OBTAINED |
| JP4462838B2 (en) * | 2002-04-19 | 2010-05-12 | 三井製糖株式会社 | Alpha wave release enhancer, agent that can lead to a relaxed state, and food and drink containing the agent |
| AU2006233640B8 (en) * | 2005-04-15 | 2011-01-06 | Keme Food Engineering Ag | Instant product |
| DE102008012295A1 (en) | 2008-03-03 | 2009-09-17 | Südzucker AG Mannheim/Ochsenfurt | Mixture for the preparation of rapidly disintegrating tablets |
| EP4260864A1 (en) | 2022-04-13 | 2023-10-18 | Bluestone Pharma GmbH | Product comprising probiotics and isomaltulose and method of its production |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1429334A (en) * | 1972-04-12 | 1976-03-24 | Sueddeutsche Zucker Ag | Process for the preparation of isomaltitol |
Family Cites Families (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1049800B (en) * | 1957-10-11 | 1959-01-29 | Süddeutsche Zucker-Aktiengesellschaft, Mannheim | METHOD FOR MANUFACTURING PALATINOSE (6-α-GLUCOSIDO-FRUCTOFURANOSE) |
| US3200039A (en) * | 1962-05-28 | 1965-08-10 | Pfizer & Co C | Non-granulated tablets with 20% sorbitol in a particle size of from about 100mu to about 2000mu |
| US3341415A (en) * | 1964-02-12 | 1967-09-12 | Warner Lambert Pharmaceutical | Pharmaceutical tablet excipients of solid particles of a binary solid solution of mannitol with a sugar |
| DE1228029C2 (en) * | 1964-05-09 | 1973-05-17 | Merck Ag E | Process for the production of tablets by pressing powder mixtures without prior granulation |
| US3446899A (en) * | 1968-01-25 | 1969-05-27 | Hoffmann La Roche | Vitamin compositions produced by direct compression |
| US3619292A (en) * | 1968-07-15 | 1971-11-09 | Penick & Ford Ltd | Tablets and method of forming |
| US4013775A (en) * | 1968-10-14 | 1977-03-22 | Cpc International Inc. | Process for preparing a sugar tablet |
| US3639169A (en) * | 1969-04-29 | 1972-02-01 | Sucrest Corp | Direct compression vehicles and method therefor |
| US3627583A (en) * | 1969-04-29 | 1971-12-14 | Sucrest Corp | Direct compression vehicles |
| US3642535A (en) * | 1970-01-21 | 1972-02-15 | American Sugar | Tabletting sugar, method of preparing compositions containing same |
| JPS4837815B1 (en) * | 1970-09-25 | 1973-11-14 | Yamanouchi Pharma Co Ltd | |
| US3961004A (en) * | 1974-04-11 | 1976-06-01 | Auburn Research Foundation | Method of tabletting using gluconolactone as the direct compression diluent |
| DE2440383B2 (en) * | 1974-08-23 | 1979-01-11 | Boehringer Mannheim Gmbh, 6800 Mannheim | Process for making tablets |
| DE2860239D1 (en) * | 1977-09-13 | 1980-12-04 | Bayer Ag | Process for the continuous isomerisation if saccharose to isomaltulose by means of microorganisms |
| JPS6054322B2 (en) * | 1977-09-30 | 1985-11-29 | 株式会社林原生物化学研究所 | Manufacturing method for molded products |
| GB2014149A (en) * | 1978-01-23 | 1979-08-22 | Cpc International Inc | Maltulose-containing syrups and process for making same |
-
1980
- 1980-10-31 DE DE8080303887T patent/DE3062775D1/en not_active Expired
- 1980-10-31 EP EP80303887A patent/EP0028905B1/en not_active Expired
- 1980-11-05 NO NO803313A patent/NO157882C/en unknown
- 1980-11-06 IE IE2305/80A patent/IE50399B1/en not_active IP Right Cessation
- 1980-11-06 CA CA000364096A patent/CA1157772A/en not_active Expired
- 1980-11-07 DK DK476180A patent/DK155713C/en not_active IP Right Cessation
-
1983
- 1983-11-21 US US06/553,867 patent/US4572916A/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1429334A (en) * | 1972-04-12 | 1976-03-24 | Sueddeutsche Zucker Ag | Process for the preparation of isomaltitol |
Also Published As
| Publication number | Publication date |
|---|---|
| NO803313L (en) | 1981-05-08 |
| IE50399B1 (en) | 1986-04-16 |
| US4572916A (en) | 1986-02-25 |
| NO157882B (en) | 1988-02-29 |
| DK155713C (en) | 1989-09-25 |
| EP0028905B1 (en) | 1983-04-13 |
| DK476180A (en) | 1981-05-08 |
| EP0028905A1 (en) | 1981-05-20 |
| DE3062775D1 (en) | 1983-05-19 |
| CA1157772A (en) | 1983-11-29 |
| IE802305L (en) | 1981-05-07 |
| NO157882C (en) | 1988-06-08 |
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| PBP | Patent lapsed |